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J. Biol. Chem., Vol. 278, Issue 41, 39941-39950, October 10, 2003

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KCl Cotransport Is an Important Modulator of Human Cervical Cancer Growth and Invasion^*

Meng-Ru Shen   ¶ ||, Cheng-Yang Chou , Keng-Fu Hsu , Yueh-Mei Hsu **, Wen-Tai Chiu **, Ming-Jer Tang **, Seth L. Alper  and J. Clive Ellory ¶

From the Departments of Pharmacology, Obstetrics and Gynecology, and ^**Physiology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan, ^¶University Laboratory of Physiology, Parks Road, University of Oxford, Oxford OX1 3PT, United Kingdom, and Molecular Medicine and Renal Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Cervical cancer is a major world health problem for women, but the pathophysiology of this disease has received scant attention. Here we show that the growth and invasion of cervical cancer cells are strongly linked the expression and activity of the KCl cotransporter (KCC), an important regulator of the ionic and cellular osmotic homeostasis. Functional assays of KCl cotransport activation by osmotic swelling, staurosporine, and N-ethylmaleimide indicate that removal of the N-terminal 117 amino acids from KCC1 produces a dominant-negative loss-of-function phenotype for KCl cotransport in human cervical cancer cells. The capability for regulatory volume decrease is much attenuated in the loss-of-function KCC mutant cervical cancer cells. The loss-of-function KCC mutant cervical cancer cells exhibit inhibited cell growth accompanied by decreased activity of the cell cycle gene products retinoblastoma and cdc2 kinase. Reduced cellular invasiveness is in parallel by reduced expression of _v3 and ₆₄ integrins, accompanied by decreased activity of matrix metalloproteinase 2 and 9. Inhibition of tumor growth in SCID mice confirms the crucial role of KCC in promoting cervical cancer growth and invasion. Thus, blockade of KCl cotransport may be a useful therapeutic adjunctive strategy to retard or prevent cervical cancer invasion.

Received for publication, July 28, 2003

^* This work was supported in part by the Wellcome Trust and Royal Society (to J. C. E.), by the National Institutes of Health (to S. L. A.), and by the National Science Council, Taiwan Grant NSC92-2320-B-006-052 and Program for Promoting University Academic Excellence Grant 91-B-FA09-1-4 (to M. R. S. and C. Y. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Exchange Fellow supported by the Royal Society and National Science Council, Taiwan. To whom correspondence should be addressed: Dept. of Pharmacology, National Cheng Kung University Medical College, Tainan 701, Taiwan. Tel.: 886-6-2353535 (ext. 5505); Fax: 886-6-2766185; E-mail: mrshen{at}mail.ncku.edu.tw.

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